In the phase 3 CLL14 trial, fixed-duration therapy with the combination of venetoclax plus obinutuzumab was superior to the combination of chemotherapy with chlorambucil plus obinutuzumab as frontline therapy in older patients with chronic lymphocytic leukemia (CLL) and comorbidities. At ASCO 2019, Kirsten Fischer, MD, Center of Integrated Oncology Cologne, Bonn, University Hospital, Cologne, Germany, presented the study results, which were published simultaneously (Fischer K, et al. N Engl J Med. 2019;380:2225-2236).
Based on these results, on May 15, 2019, the FDA approved the combination of venetoclax plus obinutuzumab as frontline treatment for a fixed duration for patients with CLL.
The fixed-duration regimen significantly improved progression-free survival (PFS), complete response rate, and minimal residual disease (MRD) negativity versus chemotherapy plus obinutuzumab and was superior in patients with poor prognostic factors, such as IGHV and TP53 mutations. This fixed-duration combination was hailed as a new standard of care by experts at the ASCO meeting.
“This study is practice-changing in the frontline setting. For most patients, we should be considering venetoclax plus obinutuzumab for frontline therapy,” commented Matthew S. Davids, MD, MMSc, Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute, Boston, MA. He emphasized the fixed-duration treatment and the high rates of MRD negativity achieved in the trial as the features that distinguish this regimen from other combinations in CLL, including the frontline combination ibrutinib plus obinutuzumab, which was approved by the FDA in January 2019 but is given as a continuing therapy.
“Fixed-duration targeted therapy combining venetoclax and obinutuzumab can be applied safely to elderly CLL patients with comorbidities. Our study showed it is superior to fixed-duration chlorambucil and obinutuzumab. Venetoclax plus obinutuzumab achieves the highest rates of MRD-negative response so far observed in a randomized prospective trial” of patients with CLL, stated Dr Fischer.
The median follow-up is 28 months, and thus far no survival difference has been seen between the 2 regimens. “It might be too early to see an effect on survival,” Dr Fischer said.
The open-label, randomized, phase 3 CLL14 clinical trial enrolled 432 treatment-naive patients (median age, 72 years) with CD20-positive CLL. Patients had to have clinically significant comorbidities, indicated by a score of >6 on the Cumulative Illness Rating Scale, or a creatinine clearance of <70 mL/min. Patients were randomized in a 1:1 ratio to venetoclax plus obinutuzumab or to chlorambucil plus obinutuzumab for twelve 28-day cycles.
Treatment arms were well balanced for demographic and disease characteristics. In total, 13.8% of the patients had TP53 deletion, mutation, or both, and 59.8% had IGHV mutation.
With a median follow-up of 28 months, the median PFS was not reached in either group. The estimated 24-month PFS was 88.2% in the venetoclax-obinutuzumab group versus 64.1% in the chlorambucil-obinutuzumab arm (P <.0001).
“MRD negativity was achieved early with venetoclax and stayed that way over time,” Dr Fischer told listeners.
Three months after treatment ended, an intent-to-treat analysis showed an MRD negativity in peripheral blood rate of 75.5% with the targeted combination versus 35.2% with chemotherapy plus obinutuzumab (P <.001); the rates of MRD in bone marrow were 56.9% versus 17.1%, respectively (P <.001).
The overall response rates were 84.7% versus 71.3%, respectively (P <.001), and the complete response rates were 49.5% versus 23.1%, respectively (P <.001).
The rates of patients with a complete response and MRD negativity in peripheral blood were significantly higher in the venetoclax plus obinutuzumab arm—42.1% versus 14.4%, respectively (P <.001); the rates in bone marrow were 33.8% versus 10.6%, respectively (P <.001).
Safety and Tolerability
At least 1 adverse event of any grade was reported in 94.5% of the patients in the venetoclax plus obinutuzumab arm and in 99.5% of those in the chlorambucil-obinutuzumab arm (total safety population, 426 patients). Adverse events leading to treatment discontinuation occurred in 16% and 15.4% of patients, respectively.
The most common grade 3/4 event was neutropenia. The rates of grade 3/4 febrile neutropenia were 5.2% and 3.7%, respectively, and rates of grade 3/4 infections were 17.5% and 15%, respectively. No patient had symptoms that met clinical criteria for tumor lysis syndrome. The rate of grade 3/4 infusion reactions was similar (9% and 10.3%, respectively). The rate of second cancers was not significantly different between the 2 treatment arms.